Severe hypoglycemic episodes are a common occurrence among diabetic patients. An important interaction between hypoglycemia and antipsychotic medications, however, has gone largely unnoticed. The risk for diabetes is doubled in schizophrenia, and hypoglycemic episodes are a common side effect of treatment for both type 1 and type 2 diabetes. Preclinical studies demonstrate cognitive impairment mediated by elevated glutamate following insulin-induced hypoglycemia. Typical antipsychotic medications such as haloperidol elevate extracellular glutamate through antagonist effects on dopamine D2 and serotonin 5HT1A receptors, while serotonin 5HT2A receptor antagonists inhibit glutamate release. Glutamate is excitotoxic through effects on ionotropic receptor channels and synergistic effects with other neurotoxic pathways activated by hypoglycemia. Haloperidol could worsen the cognitive dysfunction of insulin-induced hypoglycemia by elevating extracellular glutamate. In contrast, alternative atypical antipsychotic medications including quetiapine and aripiprazole have pharmacological properties limiting extracellular glutamate and may be neuroprotective in this setting. The objective of this application is to determine the relative effects of haloperidol, quetiapine and aripiprazole on extracellular glutamate and cognitive outcome following insulin-induced hypoglycemia. We hypothesize quetiapine and aripiprazole's more limited D2 antagonism, increased 5HT2A affinity, and 5HT1A partial agonism decrease extracellular glutamate and improve cognitive outcome compared to haloperidol. We will test this hypothesis in Specific Aim 1 by measuring extracellular glutamate in rats treated with haloperidol, quetiapine, aripiprazole or vehicle during insulin-induced hypoglycemia. We expect to observe decreased extracellular glutamate with quetiapine and aripiprazole treatment compared to haloperidol, demonstrating a neurochemically relevant but unappreciated measure distinguishing quetiapine and aripiprazole from typical psychotics. In Specific Aim 2, we will measure cognitive outcome in rat treated with haloperidol, quetiapine, aripiprazole or vehicle during insulin-induced hypoglycemia. We expect to identify improved cognition in rats treated with quetiapine and aripiprazole compared to haloperidol, demonstrating a functional improvement resulting from alternative treatment. The proposed studies are innovative in that while there is widespread recognition of each individual step comprising the risk of interaction between haloperidol and insulin-induced hypoglycemia, awareness of the resulting medical significance is limited. The clinical implication of this study is that it could immediately lead to improved safety for 35 million diabetic patients worldwide taking antipsychotic medications. PUBLI HEALTH RELEVANCE: We propose to determine the effect of the antipsychotic medications haloperidol, quetiapine, and aripiprazole on extracellular glutamate, and cognitive outcome, following insulin-induced hypoglycemia. We expect to observe decreased extracellular glutamate, and improved cognitive outcome, in rats treated with quetiapine and aripiprazole compared to haloperidol. These outcomes are important because they will demonstrate a neurochemically relevant measure distinguishing quetiapine and aripiprazole from typical antipsychotic medications which may lead to improved safety for diabetic patients taking antipsychotic medications.